This invention relates to methods and devices for inducing angiogenesis in ischemic tissue.
Tissue becomes ischemic when it is deprived of oxygenated blood. Blood may be present in such tissue, though it is not carrying oxygen. Ischemic tissue can be revived to function normally if it has remained viable despite the deprivation of oxygenated blood. Ischemia can be caused by a blockage in the vascular system that prohibits oxygenated blood from reaching the affected tissue area. Ischemia causes pain in the area of the affected tissue and in the case of muscle tissue can interrupt muscular function.
Although ischemia can occur in various regions of the body, often tissue of the heart, the myocardium, is affected by ischemia due to coronary artery disease, occlusion of the coronary artery, which otherwise provides blood to the myocardium. Muscle tissue affected by ischemia can cause pain to the individual affected. Ischemia can be treated, if a tissue has remained viable despite the deprivation of oxygenated blood, by restoring blood flow to the affected tissue.
Treatment of myocardial ischemia has been addressed by several techniques designed to restore blood supply to the affected region. Coronary artery bypass grafting CABG involves grating a venous segment between the aorta and the coronary artery to bypass the occluded portion of the artery. Once blood flow is redirected to the portion of the coronary artery beyond the occlusion, the supply of oxygenated blood is restored to the area of ischemic tissue.
Early researchers, more than thirty years ago, reported promising results for revascularizing the myocardium by piercing the muscle to create multiple channels for blood flow. Sen, P. K. et al., xe2x80x9cTransmyocardial Acupuncturexe2x80x94A New Approach to Myocardial Revascularizationxe2x80x9d, Journal of Thoracic and Cardiovascular Surgery, Vol. 50, No. 2, August 1965, pp. 181-189. Although others have reported varying degrees of success with various methods of piercing the myocardium to restore blood flow to the muscle, many have faced common problems such as closure of the created channels. Various techniques of perforating the muscle tissue to avoid closure have been reported by researchers. These techniques include piercing with a solid sharp tip wire, hypodermic tube and physically stretching the channel after its formation. Reportedly, many of these methods still produced trauma and tearing of the tissue that ultimately led to closure of the channel.
An alternative method of creating channels that potentially avoids the problem of closure involves the use of laser technology. Researchers have reported success in maintaining patent channels in the myocardium by forming the channels with the heat energy of a laser. Mirhoseini, M. et al., xe2x80x9cRevascularization of the Heart by Laserxe2x80x9d, Journal of Microsurgery, Vol. 2, No. 4, June 1981, pp. 253-260. The laser was said to form channels in the tissue that were clean and made without tearing and trauma, suggesting that scarring does not occur and the channels are less likely to experience the closure that results from healing. Aita U.S. Pat. Nos. 5,380,316 and 5,389,096 disclose another approach to a catheter based laser system for TMR.
Although there has been some published recognition of the desirability of performing transmyocardial revascularization (TMR) in a non-laser catheterization procedure, there does not appear to be evidence that such procedures have been put into practice. For example, U.S. Pat. No. 5,429,144 Wilk discloses inserting an expandable stent within a preformed channel created within the myocardium for the purposes of creating blood flow into the tissue from the left ventricle Performing TMR by placing stents in the myocardium is also disclosed in U.S. Pat. No. 5,810,836 (Hussein et al.). The Hussein patent discloses several stent embodiments that are delivered through the epicardium of the heart, into the myocardium and positioned to be open to the left ventricle. The stents are intended to maintain an open a channel in the myocardium through which blood enters from the ventricle and perfuses into the myocardium.
Angiogenesis, the growth of new blood vessels in tissue, has been the subject of increased study in recent years. Such blood vessel growth to provide new supplies of oxygenated blood to a region of tissue has the potential to remedy a variety of tissue and muscular ailments, particularly ischemia. Primarily, study has focused on perfecting angiogenic factors such as human growth factors produced from genetic engineering techniques. It has been reported that injection of such a growth factor into myocardial tissue initiates angiogenesis at that site, which is exhibited by a new dense capillary network within the tissue. Schumacher et al., xe2x80x9cInduction of Neo-Angiogenesis in Ischemic Myocardium by Human Growth Factorsxe2x80x9d, Circulation, 1998; 97:645-650. The authors noted that such treatment could be an approach to management of diffused coronary heart disease after alternative methods of administration have been developed.
The vascular inducing implants of the present invention provide a mechanism for initiating angiogenesis within ischemic tissue. The implants interact with the surrounding tissue in which they are implanted and the blood that is present in the tissue to initiate angiogenesis by various mechanisms.
Primarily, it is expected that the implants will trigger angiogenesis in the ischemic tissue by interacting in one or more ways with the tissue to initiate an injury response. The body""s response to tissue injury involves thrombosis formation at the site of the injury or irritation. Thrombosis leads to arterioles and fibrin growth which is believed to ultimately lead to new blood vessel growth to feed the new tissue with blood. The new blood vessels that develop in this region also serve to supply blood to the surrounding area of ischemic tissue that was previously deprived of oxygenated blood.
The implant devices may be formed in a variety of configurations to carry out the objectives outlined above for initiating angiogenesis. Specifically, the implants can be arranged in various ways to provide a first configuration that presents a reduced profile and a second configuration that is expanded to provide a larger profile that will irritate and place stress on the surrounding tissue into which it has been implanted. The first configuration is suitable for delivery to the tissue site and into the tissue. The second configuration is obtained after the implant is placed in the tissue. Expansion of the device to the larger profile configuration not only places stress on the tissue but serves to rupture and injure the tissue slightly as it expands. The change in profile between the first configuration and second configuration is of such a magnitude that the irritation and injury suffered by surrounding tissue upon expansion of the implant will induce an injury response that results in angiogenesis. However, the magnitude of the expansion to the second configuration is not so great that tissue becomes severely injured: function impaired and unable to heal.
Additionally, each implant embodiment serves to provide a constant source of irritation and injury to the tissue in which it is implanted, thereby initiating the healing process in that tissue that is believed to lead to angiogenesis. As tissue surrounding the implant moves, such as the contraction and relaxation of muscle tissue, some friction and abrasion from the implant occurs, which injures the tissue. The injury caused by the outside surfaces of the implants to the surrounding tissue does not substantially destroy the tissue, but is sufficient to initiate an injury response and healing which leads to angiogenesis.
Implant embodiments of the invention also serve to initiate angiogenesis by providing an interior chamber into which blood may enter, collect and thrombose. Blood that enters the implant and remains, even temporarily, tends to coagulate and thrombus. Over time, continued pooling of the blood in the interior will cause thrombosis and fibrin growth throughout the interior of the implant and into the surrounding tissue. New blood vessels will grow to serve the new growth with oxygenated blood, the process of angiogenesis.
Implant embodiments may further be prepared to initiate angiogenesis by having a thrombus of blood associated with them at the time of their implantation or inserted in the interior immediately following implantation. The thrombus of blood may be taken from the patient prior to the implant procedure and is believed to help initiate the tissue""s healing response which leads to angiogenesis.
Alternatively or in addition to a thrombus of blood, the implant devices may be associated with an angiogenic substance in a variety of ways to aid the process of angiogenesis, In embodiments having a defined interior, the substance may be placed within the interior prior to implantation or injected after the implantation of the device. The substance may be fluid or solid. The blood flow into and interacting with the interior of the device will serve to distribute the substance through the surrounding tissue area because blood entering the device mixes with and then carries away the substance as it leaves the device. Viscosity of the substance and opening size through which it passes, determine the time-release rate of the substance.
Substances may be associated with the device, not only by being carried within their interiors, but also by application of a coating to the device. Alternatively, the substance may be dispersed in the composition of the device material. Alternatively, the implant may be fabricated entirely of the angiogenic substance. Recognizing that there are many ways to attach an angiogenic substance or drug to a device, the methods listed above are provided merely as examples and are not intended to limit the scope of the invention. Regardless of the method of association, the implants of the present operation operate to distribute the angiogenic substance in surrounding tissue by the implants contact with the tissue and blood supply in that tissue area.
By way of example, the implant device may comprise a helical spring having a first configuration that is more tightly wound, having an elongated length, more coils and a reduced diameter The second configuration of the spring will provide an increased profile by increasing the diameter of the coils through shortening the length of the spring.
In another embodiment, the implant may comprise a mesh tube comprised of individual wire-like elements that are woven and arranged to allow the tube to have a first configuration that is elongated with a smaller diameter and a second configuration that is shortened in length, but correspondingly larger in diameter and profile. In yet another configuration, the implant may comprise a sheet of solid or porous material that is rolled into a tube. A first, reduced profile configuration of the tube is tightly rolled upon itself, storing potential energy that will provide resilient expansion of the rolled tube to a less tightly rolled tubular shape when released. The expanded configuration of the tube provides a second configuration of the implant that has a larger profile. In another embodiment, the implant may comprise a spine having spaced along its length several C-shaped rings that may be compressed into a smaller profile in which the rings are closed and a second configuration having an increased profile wherein the rings are opened to a C-shape. The ends of the C-shaped rings may be formed to have eyelets that meet and are concentrically arranged when the rings are closed so that a release pin can be inserted through them to hold them in their reduced profile configuration. Once the implant is placed within the tissue, the release pin may be removed permitting the rings to resiliently expand to a C configuration.
In another embodiment, the implant may have a first configuration that is uniaxial and a second configuration that is biaxial or bifurcated to provide an increased profile. The bifurcated embodiments disclosed may be comprised of single or double helical coils arranged to have a trunk portion and two leg portions. The resulting appearance is similar to a pair of pants. Alternatively, the bifurcated embodiment may be configured as two spines having loops mounted concentrically along their length, the spines being joined to several common loops at one end to form a trunk portion, and the other ends of the spine being free to form the leg portions of the implant. In both bifurcated implant embodiments, the loops or coils are interleaved while maintained in the first configuration such that they lie substantially along the same axis. In the second configuration, the spines spring apart to form a Y-shaped or bifurcated configuration presenting a larger profile to increase the injury to surrounding tissue and initiate angiogenesis.
Alternatively, the device may comprise a body that has attached thereto flexible elements configured to retain, at least temporarily, blood or angiogenic substances. An example of such an embodiment would be a small brush having an axial core member with a plurality of flexible bristles extending radially therefrom. The bristles having a natural resilience to a radially outward configuration with respect to the core. During delivery of the brush into tissue, the bristles are swept back against the core. However, after insertion, the resilient bristles return at least partially to their radially outward extending configuration, thereby placing surrounding tissue in stress and causing irritation to the tissue. The bristles are also configured to absorb, or hold within a hollow interior a drug or amount of quantity of blood. Additionally, the core member may be configured to define a hollow interior capable of holding a therapeutic substance.
One or more implants of the present invention may be applied to an area of ischemic tissue. By way of example, the implants may define a width of approximately 2 mm and a length corresponding to somewhat less than the thickness of the tissue into which it is implanted. It is anticipated that implants having a 2 mm wide profile would serve an area of ischemic tissue of approximately one square centimeter to adequately promote angiogenesis throughout the surrounding region of tissue yet avoid altering the movement of the tissue due to a high density of foreign objects within a confined region of tissue.
The implants are delivered directly into the subject tissue without preforming a channel by removal of tissue such as by coring or ablation by a laser. The delivery devices, while loaded with the implant, operate to pierce and penetrate the tissue in a single driving motion. While the delivery device is penetrating the tissue, the implant is released and expanded into its second configuration within the tissue. The expanded implant is left behind as the delivery device is withdrawn. Upon expansion of the device, the surrounding tissue may tear and become injured as it is pushed aside by the implant. The stressed tissue also tries to recoil around the device and may herniate through openings in the structure of the device. It is not important that the implant maintain an open channel through the tissue for blood to flow. The objective of the implant is to trigger angiogenesis , so that new blood vessels will be created to introduce blood flow to the region.
The devices may be implanted percutaneously and transluminally, thoracically or surgically by a cut down method. In the case of implants placed within myocardial tissue of the heart, delivery systems are disclosed for percutaneously accessing the left ventricle of the heart and penetrating and delivering the implant into the myocardium.
It is an object of the present invention to provide a method of promoting angiogenesis within ischemic tissue.
It is another object of the present invention to provide a method of promoting angiogenesis by implanting a device within ischemic tissue.
It is another object of the present invention to provide a method of promoting angiogenesis by causing thrombosis in the area of ischemic tissue.
It is another object of the present invention to provide a process of promoting angiogenesis within ischemic myocardial tissue of the heart.
It is another object of the invention to provide an implant suitable for implantation within tissue of the human body.
It is another objective of the present invention to provide an implant delivery system that is safe and simple to use while minimizing trauma to the patient.
It is another object of the invention to provide an implant that will irritate tissue that surrounds the implant to initiate a healing response that leads to angiogenesis.
It is another object of the invention to provide an implant having a small profile first configuration and large profile second configuration after implantation into tissue such that the implant places stress on the surrounding tissue.
It is another object of the invention to provide an implant that is configured to have associated with it an angiogenic substance that promotes angiogenesis within tissue surrounding the implant.
It is another object of the invention to provide an implant configured to interact with blood present in the tissue into which the implant is inserted.
It is another object of the invention to provide an implant that defines an interior into which blood can enter and thrombose.
It is another object of the invention to provide an implant to which a thrombus of blood or an angiogenic substance can be inserted before or after the implant has been inserted into tissue.